Defects in Germinal Center Selection in SLE

Abstract

Germinal centers (GCs) are the primary site at which clonal expansion and affinity maturation of B cells occur. B cells encounter antigen and receive T cell help in the GC light zone (LZ) and then migrate to the dark zone where they proliferate and undergo somatic mutation before cycling back to the LZ for further rounds of selection. Tolerance to autoantigens is frequently lost de novo as GC B cells undergo class switching and somatic mutation. This loss of tolerance is regulated by a variety of mechanisms including cell death, failure to compete for T cell help, and failure to differentiate into effector cells. Systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nucleic acid antigens. While defects in tolerance occur in the naïve repertoire of SLE patients, pathogenic autoantibodies also arise in the GC by somatic mutation from non-autoreactive precursors. Several B cell defects contribute to the loss of GC tolerance in SLE, including polymorphisms of genes encoded by the Sle1 locus, excess TLR7 signaling, defects in FcRIIB expression, or defects of B cell apoptosis. Extrinsic soluble factors, such as Type-1 IFN and B cell-activating factor, or an increased number of T follicular helper cells in the GC also alter B cell-negative selection. Finally, defects in clearance of apoptotic debris within the GC result in BCR-mediated internalization of nucleic acid containing material and stimulation of autoantibody production by endosomal TLR-driven mechanisms.

Keywords: B cell; SLE; autoimmunity; germinal center; tolerance mechanisms.

Figure 1

Schematic of the germinal center: germinal centers consist of two major anatomic regions. The major cell types in the light zone (LZ) and dark zone (DZ) are shown. B cell centrocytes undergo selection in the light zone and then migrate to the dark zone where the B cell centroblasts proliferate and undergo somatic mutation before cycling back to the light zone. After several cycles, B cells differentiate into memory cells or plasma cells and exit the germinal center. Defects in germinal center cells or functions that result in spontaneous germinal center formation and loss of tolerance to nucleic acid antigens are shown on the right.